Day, Misty C. MD1; Barton, John R. MD2; O’Brien, John M. MD2; Istwan, Niki B. RN3; Sibai, Baha M. MD4
From the Departments of 1Obstetrics and Gynecology, University of Kentucky, Lexington, Kentucky; 2Maternal-Fetal Medicine, Central Baptist Hospital, Lexington, Kentucky; 3Clinical Research, Matria Healthcare, Marietta, Georgia; and 4Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio.
Presented at the Annual Meeting of the American College of Obstetricians and Gynecologists, San Francisco, California, May 7–11, 2005.
Corresponding author: John M. O’Brien, MD, Director, Perinatal Diagnostic Center, Central Baptist Hospital, 1740 Nicholasville Road, Lexington, KY 40503; e-mail: firstname.lastname@example.org.
OBJECTIVE: To estimate the incidence and effect of pregnancy-related hypertensive conditions on multiple gestations.
METHODS: Women with 1–4 fetuses enrolled in an outpatient perinatal services program at 28 or more weeks of gestation were identified. Those without a prior diagnosis of hypertension at enrollment and who delivered at more than 28 weeks of gestation were included in the analysis. The incidence of all pregnancy-related hypertensive conditions, diagnosis of severe hypertensive conditions (hemolysis, elevated liver enzymes and low platelets syndrome; disseminated intravascular coagulation; eclampsia; low platelets; renal failure; and abruption), and interventional delivery related to hypertension were estimated, and compared according to fetal number.
RESULTS: Data were analyzed for 34,374 singleton, twin, triplet, and quadruplet gestations. The incidence of pregnancy-related hypertensive conditions increased with multifetal gestations as compared with singletons (12.7–19.6% for multifetal gestations compared with 6.5% for singletons, P < .001). The incidence of severe pregnancy-related hypertensive conditions was significantly increased in twin (1.6%) and triplet (3.1%) gestations as compared with singletons (0.5%, P < .001). Quadruplet pregnancies were not significantly higher than triplet gestations for these complications. The need for early delivery related to hypertension was greater with increasing fetal number through triplet gestations. By logistic regression, higher fetal number, nulliparity, and advanced maternal age were each independently associated with the development of pregnancy-related hypertensive conditions.
CONCLUSION: Mild and severe pregnancy-related hypertensive disease increases progressively with advancing fetal number from singleton to triplets but is not further increased in quadruplet pregnancies. Multifetal pregnancies should be observed closely for onset of gestational hypertensive disease.
LEVEL OF EVIDENCE: II-2
The incidence of multifetal gestations has increased dramatically, with a 52% increase in the number of twin births recorded from 1980–97 and a 404% increase in triplets and higher order multiples.1 Factors contributing to this trend are the increase in assisted reproductive techniques and women deferring child bearing until an older age. Unfortunately, multifetal gestations are at increased risk for spontaneous abortion, congenital malformations, reduced birth weight, and prematurity; and as the number of multifetal gestations increases, so does the incidence of maternal and fetal morbidity.
Prior studies have evaluated the risk of maternal morbidity associated with multiple gestations including higher rates of anemia, diabetes, premature rupture of membranes and cesarean delivery.2–6 Preeclampsia and other hypertensive disorders are also more commonly observed.2–8 Most of these prior studies have focused on comparisons only between singleton and twin pregnancies and many do not delineate between mild and severe hypertensive disease. The purpose of this study was to estimate the incidence of both mild and severe forms of pregnancy-related hypertensive conditions in multifetal gestations, including higher-order multiples.
MATERIALS AND METHODS
An analysis of prospectively collected clinical information from women enrolled in outpatient perinatal programs was performed. The population of women involved in the present investigation was evaluated and observed in an outpatient surveillance program of Matria Healthcare, Inc. between May 1995 and May 2004. Data from these pregnancies were collected prospectively and entered into a large database. The women of this population included in the study group met the following inclusion criteria: 1) had a multifetal pregnancy with either a twin, triplet, or quadruplet gestation, 2) initially participated in the program at 28 weeks or more of gestation, 3) did not have a diagnosis of hypertension or preeclampsia at initial evaluation, and 4) delivered at more than 28 weeks of gestation with a known pregnancy outcome. The control group consisted of women who were enrolled in the same outpatient monitoring program during the same time interval who: 1) had a singleton gestation, 2) had a known pregnancy outcome, and 3) had a similar gestational age at onset of observation in the program as 28 weeks or more of gestation and delivered at more than 28 weeks of gestation with a known outcome.
The primary outcome variable of the study was the diagnosis of any pregnancy-related hypertensive conditions during observation, including gestational hypertension; mild or severe preeclampsia; hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome; disseminated intravascular coagulation (DIC); eclampsia; low platelet count; abruption placenta; and renal failure.9 Mild pregnancy-related hypertensive disease consisted of mild preeclampsia or mild gestational hypertension. Gestational hypertension was defined as development of elevated blood pressure without proteinuria after 20 weeks of gestation. Preeclampsia was defined as blood pressure of 140 mm Hg systolic or higher or 90 mm Hg diastolic or higher after 20 weeks of gestation, with proteinuria (> 1+ on 2 occasions by dipstick). Severe pregnancy-related hypertensive disease was defined as either 1) severe hypertension (≥160/110 mm Hg on 2 occasions) with proteinuria, 2) mild hypertension with severe proteinuria (≥ 3+), 3) hypertension with the development of thrombocytopenia, HELLP syndrome, renal failure, or disseminated intravascular coagulation, or 4) development of eclampsia. These definitions differ slightly from the American College of Obstetricians and Gynecologists criteria because only urinary dipstick data were available rather than 24-hour urine specimens, but these criteria were applied consistently to all groups.
The need for interventional delivery either by induction of labor or cesarean as a result of these diagnoses was also recorded. The incidence of these outcomes was estimated and compared by fetal number. Statistical calculations were performed using analysis of variance for normally distributed continuous variables; when assumptions of normality were violated, the Kruskal-Wallis test statistic was used. Pearson’s χ2 and Fisher exact tests were used to determine differences among categorical data. Significant results were defined as those with P < .05. Logistic regression analysis was performed to estimate the odds ratio for development of pregnancy-related hypertensive conditions among the different study populations. All women in the study consented for participation in research investigations. This study was also approved by the institutional review board of Central Baptist Hospital.
From a database of 101,348 women managed between May 1995 and May 2004 through Matria Healthcare, Inc., a study sample composed of 9,593 women with multiple gestations was obtained after applying inclusion criteria. Of these, 6,859 women had twin gestations, 2,545 had triplet gestations, and 189 had quadruplet gestations. This study group was compared with a control group of 24,781 women with singleton pregnancies (a 2.6:1 ratio). Maternal demographics for these groups are presented in Table 1. The incidence of nulliparity and advanced maternal age were more common in women with multifetal gestations. Furthermore, the frequency of tobacco abuse was higher in women with a singleton gestation.
Table 2 outlines the incidence of pregnancy-related hypertensive conditions in singleton compared with multifetal gestations. The incidence of hypertensive conditions is greater in twin, triplet, and quadruplet pregnancies (12.7%, 20.0%, and 19.6%, respectively) as compared with singletons (6.5%, all P < .001). In addition, severe hypertensive conditions are greater (12.7% twin, 16.3% triplet) compared with singletons (7.7%, P < .001 each), and they had a higher rate of interventional delivery for hypertensive disease.
Table 3 presents the incidence of severe complications associated with pregnancy-related hypertensive conditions with increasing fetal number. Most importantly, the incidences of HELLP syndrome and low platelets were observed more commonly with advancing fetal number. Quadruplet pregnancies did not demonstrate an increase in pregnancy-related hypertensive conditions, mild or severe, nor did they require more frequent intervention for these conditions compared with triplet gestations.
Logistic regression analysis was performed using development of pregnancy-related hypertensive conditions as the dependent variable. These results are presented in Table 4. Nulliparity, an increase in fetal number, and advanced maternal age were significantly associated with development of pregnancy-related hypertensive conditions, whereas tobacco use and marital status were not.
The incidence of pregnancy-related hypertensive conditions is greater in twin, triplet and quadruplet pregnancies compared with singleton gestations. We observed that women with a twin gestation have an approximately 2-fold increase in the incidence of pregnancy-related hypertensive disease, and triplet gestations have a 3-fold increase. These results are in agreement with other studies comparing outcomes in multifetal gestations.2–8 Our data further attempt to provide novel information regarding differing severity of gestational hypertensive disease as well as assessing the need for intervention (a PubMed search was performed on “multiple gestation and hypertensive disease,” for articles in English from January 1966 to July 2005). Most notably, the rate of severe gestational hypertensive was estimated as 3-fold higher for twins and 6-fold higher for triplets than our singleton controls.
The strength of this study is the large data set, increasing the reliability of our findings. We included 9,593 sets of multiples, 2,734 of which were triplet or quadruplet gestations. Most other studies to date have included fifty or fewer triplet gestations.6–8 Furthermore, we were able to perform a regression analysis to identify which risk factors remain significant in assessing the risk of hypertensive disease with higher-order multiple gestations. We found nulliparity and increasing fetal number to be the most predictive variables in the model studied.
We found no statistically significant difference in severe pregnancy-related hypertensive conditions in quadruplets as compared with singletons and no further increase in the risk of any pregnancy-related hypertensive disease from triplets to quadruplets. Despite data on more than 150 sets of quadruplets, our study population may not have had adequate size to identify differences between groups or may not have evaluated pregnancies at a sufficiently early gestational age. Another possible explanation for these findings is the difference in gestational age at delivery between these groups. Quadruplet pregnancies may deliver so greatly preterm on average that they do not have sufficient prolongation of pregnancy to allow for the development of severe disease. Finally, we also speculate that the hemodynamic changes of pregnancy may be sufficiently different in quadruplet gestations that these patients have a limited capacity to mount a hypertensive response.
The greater incidence of hypertensive conditions in multifetal gestations has a remarkable effect on pregnancy outcome. Sibai et al7 compared outcomes of twin pregnancies that developed hypertensive disorders to singletons. In this study, women with twin pregnancies and gestational hypertension were more likely than singleton mothers to deliver at less than 35 weeks, were more likely to have a small for gestational age infant, and were more likely to suffer a fetal death. As the risk of hypertensive disorders increases with increasing fetal number, so does the risk of comorbidities such as preterm delivery. Our data show women with a multiple gestation and hypertensive disease require intervention significantly more often compared with singletons.
Limitations to this study must be noted. The population identified is inherently at higher risk for early delivery, because data were collected from a group of patients undergoing outpatient surveillance for preterm birth. Therefore, selection bias may have occurred. In reviewing the demographic data, different characteristics were identified among study groups. Women with multifetal gestations are more likely to be married, nulliparous, and of advanced maternal age than women with singletons. They are also less likely to abuse tobacco. Importantly, however, tobacco abuse was not found to be protective for the development of hypertensive disease in multifetal pregnancies as it has in other studies.10 Finally, this data set does not allow for evaluation of potential confounding variables. For instance, data regarding the use of assisted reproduction techniques or chorionicity of the multifetal gestations were not available for all patients. Savvidou and colleagues,11 however, found no significant difference in the incidence of preeclampsia in monochorionic compared with dichorionic twin placentation.
Despite these concerns, our study shows a statistically significant increase in mild and severe forms of pregnancy-related hypertensive disease in multifetal gestations. The risk of this complication does not seem to increase further significantly after triplets. More intensive surveillance seems warranted to promptly diagnose and intervene appropriately for pregnancy-related hypertensive conditions in multifetal gestations.
1. Martin JA, Park MM. Trends in twin and triplet births: 1980-97. National Vital Statistics Reports 1999;47:1–16.
2. Wen SW, Demissie K, Yang Q, Walker MC. Maternal morbidity and obstetric complications in triplet pregnancies and quadruplet and higher-order multiple pregnancies. Am J Obstet Gynecol 2004;191:254–8.
3. Walker MC, Murphy KE, Pan S, Yang Q, Wen SW. Adverse maternal outcomes in multifetal pregnancies. BJOG 2004;111:1294–6.
4. Malone FD, Kaufman GE, Chelmow D, Athanassiou A, Nores JA, D’Alton ME. Maternal morbidity associated with triplet pregnancy. Am J Perinatol 1998;15:73–7.
5. Albrecht JL,Tomich PG. The maternal and neonatal outcome of triplet gestations. Am J Obstet Gynecol 1996;174:1551–6.
6. Buhling KJ, Henrich W, Starr E, Lubke M, Bertram S, Siebert G, et al. Risk for gestational diabetes and hypertension for women with twin pregnancy compared to singleton pregnancy. Arch Gynecol Obstet 2003;269:33–6.
7. Sibai BM, Hauth J, Caritis S, Lindheimer MD, MacPherson C, Klebanoff M, et al. Hypertensive disorders in twin versus singleton gestations. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 2000;182:938–42.
8. Mastrobattista JM, Skupski DW, Monga M, Blanco JD, August P. The rate of severe preeclampsia is increased in triplet as compared to twin gestations. Am J Perinatol 1997;14:263–5.
9. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1–S22.
10. Lain KY, Powers RW, Krohn MA, Ness RB, Crombleholme WR, Roberts JM. Urinary cotinine concentration confirms the reduced risk of preeclampsia with tobacco exposure. Am J Obstet Gynecol 1999;181:1192–6.
11. Savvidou MD, Karanastasi E, Skentou C, Geerts L, Nicolaides KH. Twin chorionicity and pre-eclampsia. Ultrasound Obstet Gynecol 2001;18:228–31.
Figure. No caption available.